Stroke is a leading cause of death in the United States, following cardiovascular disease and cancer, and is also the leading cause of physical disability among elderly patients. The current standard in stroke rehabilitation is intense physical therapy. The overall goal of this fellowship is to explore innovative rehabilitation techniques that optimize neuronal plasticity in motor centers. Because of the extensive influence of the visual system on the motor system, we propose to explore the potential of using visually-based feedback to facilitate activation of motor cortex via Hebbian mechanisms. By using virtual reality to alter visual feedback, we plan to test the hypothesis that exaggerating a discrepancy between movement and visual feedback of that movement will increase excitability of the motor cortex. We will test this principle in healthy subjects and in patients with chronic stroke. If successful, our data may have important implications not only in chronic stroke patients but also for patients in the acute stroke phase, who have the greatest potential for neural plasticity. We will also test the effects of feedback on the crossed and uncrossed corticospinal pathways of both hemispheres to fully map anatomical loci onto the neurophysiological changes produced by augmented visual feedback. We hypothesize that exaggerating error in the visual domain during finger flexion performed by healthy subjects will increase transcranial magnetic stimulation (sTMS)-induced motor evoked potentials (MEPs) in the stationary hand (relative to veridical feedback). Our preliminary data suggest that this effect may be produced in the motor cortex ipsilateral to the moving hand, potentially mediated by crossed corticospinal pathways. We will further test interhemispheric interactions by using repetitive transcranial magnetic stimulation (rTMS) to diminish interhemispheric inhibition (IHI) of the primary motor cortex to test if this will enhance the excitability of the disinhibited motor cortex. Last, we will test if augmented feedback will also increase the excitability of motor cortex in chronic stroke patients. Our preliminary data suggest that the motor cortex of the lesioned hemisphere may be susceptible to such neuroplastic changes. If successful, the proposed approach will pave the way for development of novel feedback-based approaches in stroke rehabilitation by selectively bolstering contralateral and ipsilateral motor pathways, thus optimally remapping cortical neural circuits. It is vital to establish a strong evidence-based understanding of which forms of stroke rehabilitation therapy are truly effective. Altering visual feedback via virtual reality may be a robust way of augmenting the sensorimotor system of acute and chronic stroke patients. Throughout this fellowship period, the primary objective is to explore this technique in hopes of determining a novel comprehensive approach to stroke rehabilitation, thus aiding therapists in structuring training routines for their patients to facilitate functional recovery following stroke. PUBLIC HEALTH RELEVANCE: As the elderly population in the United States skyrockets throughout the next decade, neurological disorders such as stroke will unfortunately become more prevalent. In addition to increasing awareness and instituting stroke prevention programs, we must also focus our efforts on perfecting current stroke rehabilitation techniques. It is vital to establish a strong evidence-based understanding of which forms of therapy may work, why they may work, and for whom they may be most beneficial.